HOXA13
protein-codinghomeobox A13, the group of HOXL subclass homeoboxes
Gene summary
In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. Expansion of a polyalanine tract in the encoded protein can cause hand-foot-uterus syndrome, also known as hand-foot-genital syndrome. [provided by RefSeq, Jul 2008]
- HOX1J
- HOX1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007698
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007698
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007698
Submitter: ClinGen
The *HOXA13* gene (OMIM:142959) is located on chromosome 7 at 7p15.2 and encodes a sequence-specific, AT-rich binding transcription factor. *HOXA13* is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis. Two disease entities have been reported in association with this gene: hand-foot-genital syndrome (MONDO:0007698) and Guttmacher syndrome (MONDO:0008301). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in phenotypic variability and inheritance pattern between hand-foot-genital syndrome and Guttmacher syndrome. Therefore, the following disease entities have been lumped into one disease entity: hand-foot-genital syndrome (MONDO:0007698). The *HOXA13* gene was first reported in relation to autosomal dominant hand-foot-genital syndrome in 1997 (Mortlock & Innis 1997, PMID: 9020844). Hand-foot-genital syndrome (MONDO:0007698) is characterized by the following symptoms: distal limb malformations (Bilateral thumb and great-toe hypoplasia) and urogenital defects (abnormality of the uterus, bicornuate uterus, hypospadias). Distal limb malformations appear at 100% penetrance, while urogenital defects are 50% penetrant. Evidence supporting this gene-disease relationship includes case-level data and experimental data. There are at least 50 individuals with hand-foot-genital syndrome reported in literature, 14 of which were scored in this curation (Goodman et al., 2000, PMID: 10839976; Debeer et al., 2002, PMID: 12414828; Frisen et al., 2003, PMID: 12676922; Innis et al., 2004 , PMID: 15385446; Utsch et al., 2007, PMID: 17935235; Jorgensen et al. 2010, PMID: 19591980; Owens et al., 2013, PMID: 23532960). Most of the pathogenic variants are polyalanine expansions. The length of the expansion appears to correlate with the severity of the symptoms (PMID: 17935235). The curation also includes heterozygous missense and nonsense variants. Supporting experimental evidence includes biochemical function (Chip-Seq in mouse knockouts; Sheth et al., 2016, PMID: 27974206), functional alteration (COS-T cell transfection with mutant *HOXA13*, PMID: 17935235), as well as newt and mouse models. Both models showed an absence of digit formation - a limb phenotype consistent with human cases (PMID: 15385446; Takeuchi et al., 2022, PMID: 35274676). Polyalanine expansion knock-in in the mouse showed normal levels of Hoxa13 RNA, but reduced protein levels, which is suggestive of protein instability. In summary, there is definitive evidence to support the relationship between *HOXA13* and hand-foot-genital syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date July 22nd, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0008301
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007698
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007698
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007698
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Genitourinary; Musculoskeletal; Renal
Intervention: Renal
Rationale: The disorder may be recognizable in the majority of individuals, but individuals are at risk of renal findings such as unrecognized vesicoureteral reflux, which can cause renal damage, and prophylactic/treatment measures can be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HOXA13 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000522.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 6 | 61 | 3 | 70 | ||
| missense | 1 | 2 | 130 | 11 | 144 | |
| nonsense | 3 | 1 | 1 | 5 | ||
| start loss | 0 | |||||
| frameshift | 1 | 2 | 2 | 5 | ||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 5 | 5 | 139 | 72 | 3 | 224 |
Highest pathogenic variant AF is 0.0000056001704
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000513.2 | 2 | MANE Select | |
| Ensembl | ENSP00000497112.1 | 2 | MANE Select |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| hoxa13a | Danio rerio | Structure: melanocyte Quality: disorganized abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- skeletal system development
- regulation of transcription by RNA polymerase II
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA binding
- sequence-specific DNA binding
Cellular Component
- nucleus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000222753
- Coding exons
- 2
- Length
- 6604
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.558 | 143 | 163 | 0.877 | 0.00000775 | 2461 |
| Missense (PolyPhen) | 39 | 56.4 | 0.69148 | 731 | ||
| Synonymous | -1.09 | 81 | 69.4 | 1.17 | 0.00000358 | 834 |
| Loss of Function | 2.89 | 0 | 9.73 | 0.00 | 4.23e-7 | 123 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Sequence-specific, AT-rich binding transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior- posterior axis.;
- Disease
- DISEASE: Hand-foot-genital syndrome (HFG) [MIM:140000]: A disorder characterized by limb and genitourinary anomalies. Clinical features include small feet with unusually short great toes and abnormal thumbs. Females with the disorder have duplication of the genital tract. {ECO:0000269|PubMed:10839976, ECO:0000269|PubMed:12073020, ECO:0000269|PubMed:24934387, ECO:0000269|PubMed:26590955}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Guttmacher syndrome (GUTTS) [MIM:176305]: Dominantly inherited combination of distal limb and genital tract abnormalities. It has several features in common with hand-foot- genital syndrome, including hypoplastic first digits and hypospadias. Typical features not seen in hand-foot-genital syndrome include postaxial polydactyly of the hands and uniphalangeal second toes with absent nails. {ECO:0000269|PubMed:11968094}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.585
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |